Neuropsychiatric disorders have a net lifetime incidence of approximately 1-in-6 worldwide and the World Health Organisation ranks schizophrenia, bipolar disorder and depression 9th, 6th and 1st respectively in the global tables for Years Living with Disability. These disorders thus represent a very substantial unmet medical need and societal impact.
There is strong evidence for these related disorders having a substantial and overlapping genetic component. This evidence comes from multiple lines of enquiry. Genome-wide association studies indicate that at least 25% of the risk is polygenic—the sum effect of a large number of common, ancient variants each conferring a very modest incremental risk [1]. In addition to these modest effects, molecular cytogenetic, copy number variant and now sequence level analysis, has identified rare mutations of high impact in genes of biological plausibility. This second class of genes is well suited to mechanistic analysis.
The DISC1 (Disrupted in schizophrenia 1) gene is one of the best validated genes in this category, first identified as a putative risk factor because it is directly disrupted by a chromosomal t(1;11) translocation that co-segregates with major mental illness in a large family from Scotland [2].
DISC1 is a molecular scaffold protein which interacts with, and modulates, multiple proteins that play critical roles in, for example, cAMP, wnt, GABA and NMDA receptor signalling, in mitochondrial and synapse biology, in neurodevelopment, in cellular stress, in neural stem cell growth and differentiation, and in neuronal migration [3]. Thus, the DISC1 complex has the potential to regulate pathways that underpin mental illness.
Understanding the detailed cell biology of DISC1, how this is altered in mental illness and identifying corrective strategies, could transform current thinking about routes toward novel therapeutic targets or biological markers for major mental conditions. Additionally, a novel pharmacologic means of selectively manipulating the levels of DISC1 protein in vivo would allow the role of DISC1 to be evaluated in key aspects of brain development and function [4].